Within this application several publications are referenced by Arabic numerals within parentheses. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entirety are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Granulocytes are key components of at least two host defense systems against opportunistic microbial infection. In one of these systems, the polymorphonuclear leukocytes (PMNs) produce reactive oxygen intermediates which directly or indirectly destroy invading microorganisms. The other system depends on mechanisms which are independent of the respiratory burst (1-3). Neutrophil-derived proteins have long been implicated as components of this respiratory burst-independent microbicidal pathway (4-6). One group of low molecular weight (less than 4 kD) human neutrophil antibiotic peptides, called defensins, have been sequenced and shown to be localized immunohistochemically to azurophil granules (7). These peptides demonstrate in vitro antibacterial, antifungal, and antiviral effects which are highly dependent on many factors, including pH, ionic strength, and calcium or magnesium concentration. Additionally, the mode of action of these peptides and their actual contribution to in vivo antimicrobial activity are a matter of debate.